Brain edema is a clinical disorder that significantly contributes to mortality and morbidity in patients with stroke, trauma and other forms of neurological disorders. While it is well-known that vasogenic edema is a result of the breakdown of blood-brain barrier (BBB) permeability and function, little is known about the cellular and molecular mechanisms that underlie the injury and repair process of endothelial and glial cells, the major cell types that constitute the barrier, and the metalloproteinases (MMPs), the extracellular matrix components. Our working hypothesis is that oxidative stress, generated during ischemia and reperfusion and during thrombolytic therapy, causes BBB dysfunction by activation of MMPs and microglia. These processes will exacerbate injury and retard repair of the cells (endothelium and astrocytes) that constitute the BBB. This Program consists of three interactive projects and two supporting cores. Project 1 investigates the role of oxidative stress on MMP activation and its association with BBB dysfunction in mice after transient focal stroke. Project 2 elucidates the repair mechanism following the initiation of cellular damage after cerebral ischemia Project 3 elucidates the role of oxidative stress and inflammation on microglia activation and endothelial cell injury after cerebral schema. We believe these are novel studies that will provide insights into the oxidative mechanisms on BBB dysfunction after cerebral ischemia the long-term goal of these studies is to develop therapeutic interventions that target the BBB function for stroke patients.